Search

Over the years the nomenclature of thymomas has been debated regarding the best manner in which these tumors should be grouped. In every schema presented thus far, the main issue has been the presence or lack of lymphocytes and accordingly, the tumors have been place into a specific category. However, even though this concept applies for most of the cases, there are numerous tumors that do not necessarily fit into those categories as either the thymomas show another cellular proliferation associated with the epithelial cells or the epithelial cell themselves are arranged in a pattern that departs from the conventional features of the classic thymoma. Herein we will emphasize those features, which in some circumstances, mainly with small mediastinoscopic biopsies may pose a considerable problem in interpretation. We do consider that the most important issue is to be familiar with the different growth pattern that these tumors may show in order to avoid misdiagnosis. In addition, we consider that regardless of the growth pattern or cellular composition of the tumor, it is highly recommended that these tumors just like any other be carefully sampled and properly stage. Although we are fully aware of the different growth pattern and specific cellular details that thymoma may show, the discussion of each one of those tumors is beyond the scope of this review. Therefore, we have placed more emphasis in those, which in our judgment are more commonly encountered in the daily practice.

The interpretation of biopsy specimens in the diagnosis of thymoma is a subject that is generally not addressed in the literature. Even though the diagnosis of thymoma may seem to be an easy step in the assessment of these tumors, in reality, it is the biopsy specimen interpretation that will be use to determine course of action in any particular patient. It may determine whether a patient is a surgical candidate or on the contrary whether a patient may be benefited the most by medical therapy. In addition, there may be conditions in which all that is required is surgical resection without any further treatment, and that the evaluation of those conditions does not necessarily required the careful pathologic staging that thymomas need. In addition, it is important to highlight that in small biopsies, there are limitations not only in terms of the cellularity and other features that may not be present in such biopsy but also the limitation in term of immunohistochemical interpretation. Herein we have attempted to highlight numerous tumoral conditions that are frequently encountered in the daily practice of mediastinal pathology, some of them pose significant problems in separating them from thymomas. Needles to say, the entire spectrum of mediastinal pathology that may at any given time mimic thymoma is well beyond the scope of this review. Furthermore, we also herein emphasize the need for proper clinical and radiologic information and correlation in order to lead to a better interpretation of the biopsy specimen. The emphasis in this review is on thymoma and their possible pitfall and shortcomings while evaluating small biopsy specimens.

Sixty-four cases of sarcomatoid pleural mesothelioma represent the basis of this study. The patients are 51 men and 13 women between the ages of 42 and 79 years, who presented with symptoms of chest pain, cough, and weight loss. Diagnostic imaging showed the presence of diffuse pleural thickening with encasement of the lung parenchyma in all the cases. All patients had surgical resection via extrapleural pneumonectomy. By immunohistochemistry, all cases were positive for cytokeratin AE1/AE3; however, reactivity with other markers including keratin 5/6, calretinin, and D2-40 was seen in different proportions, whereas a few cases showed positive staining for GATA3, WT1, and p40. All tumors were negative for carcinomatous epitopes (carcinoembryonic antigen, CD15, and TTF1). Our findings show that even though the use of immunohistochemical stains plays an important role in the final interpretation, the best results are accomplished by a global interpretation of clinical, radiographical, and immunohistochemical findings. It is also important to highlight that it does not seem to be a single immunohistochemical stain that is pathognomonic of sarcomatoid mesothelioma and that some other stains that are commonly used for other tumors may also show positive staining in a small percentage of sarcomatoid mesotheliomas.

Introduction Immune infiltration in lung adenocarcinomas (LUADs) has been associated with response to immune checkpoint inhibitors. Clinical features underlying differential responses of patients with LUADs to immunotherapy are not well understood. Here, we analyzed the association between LUAD immune infiltration and clinicopathologic variables. Materials and Methods Intratumoral CD3, CD8, and CD68 cell densities (tumor-associated immune cells [TAICs]) were immunohistochemically assessed in 146 surgically resected LUADs. LUADs were classified into 2 groups, low and high TAICs, based on the median values of cell densities for CD3, CD8, and CD68. Somatic mutation burden and driver gene mutation status were analyzed in a subset of the cases (n = 92). We statistically analyzed the association between the TAIC groups and various clinicopathologic and molecular variables by using the χ2/Fisher and Wilcoxon sum tests and multivariable logistic regression models. Results Patient gender, tumor size, and STK11 mutations were significantly associated with TAIC levels in LUAD. Female patients exhibited significantly elevated TAIC levels (P = .005) compared with male patients. Tumor size was inversely associated with TAIC levels (P = .012). STK11 mutated tumors were associated with lower TAICs (P = .008). Higher TAICs were consistently observed in female patients with LUADs after adjusting for stage, tumor size, and age. Multivariable regression models confirmed female gender as an independent variable associated with TAIC levels in LUAD (P = .0141). Conclusion Immune infiltration in LUADs was significantly higher in female patients, warranting further exploration into the association between this clinical variable and immunotherapeutic response in LUAD.

Three cases of primary giant cell tumors of the lung akin to those described in the soft tissues are presented. The patients are 3 men between the ages of 43 and 54 years who presented with nonspecific symptoms of cough, chest pain, and shortness of breath. None of the patients had any prior history of malignancy anywhere else. Diagnostic imaging disclosed the presence of an intrapulmonary mass. All the patients underwent lobectomy. Grossly, the tumors were described as solid, slightly hemorrhagic, and measuring between 1.8 and 2.4 cm in greatest diameter. Histologically, the tumors were characterized by a dual population of multinucleated giant cells admixed with a mononuclear proliferation. Nuclear atypia was mild to moderate, and mitotic activity varied but was under 5 mitotic figures per 10 high power fields. Immunohistochemical stains showed positive staining for vimentin, CD68, and cathepsin K, whereas the tumors were negative for keratin, TTF-1, p40, S-100 protein, and SABT-2. Clinical follow-up was obtained in 2 patients who have remained alive and without evidence of recurrence or metastasis up to 12 months after surgery. One patient was lost to follow-up. The current neoplasms represent a tumor that to the best of our knowledge has not been reported as a primary neoplasm of the lung. The cases herein described represent an unusual occurrence and should be maintained in the differential diagnosis of primary pulmonary tumors rich in multinucleated giant cells.

Introduction CD73 is a membrane-bound enzyme crucial in adenosine generation. The adenosinergic pathway plays a critical role in immunosuppression and in anti-tumor effects of immune checkpoint inhibitors (ICI). Here, we interrogated CD73 expression in a richly annotated cohort of human lung adenocarcinoma (LUAD) and its association with clinicopathological, immune, and molecular features to better understand the role of this immune marker in LUAD pathobiology. Materials and methods Protein expression of CD73 was evaluated by immunohistochemistry in 106 archived LUADs from patients that underwent surgical treatment without neoadjuvant therapy. Total CD73 (T +) was calculated as the average of luminal (L +) and basolateral (BL +) percentage membrane expression scores for each LUAD and was used to classify tumors into three groups based on the extent of T CD73 expression (high, low, and negative). Results CD73 expression was significantly and progressively increased across normal-appearing lung tissue, adenomatous atypical hyperplasia, adenocarcinoma in situ, minimally invasive adenocarcinoma, and LUAD. In LUAD, BL CD73 expression was associated with an increase in PD-L1 expression in tumor cells and increase of tumor-associated immune cells. Stratification of LUADs based on T CD73 extent also revealed that tumors with high expression of this enzyme overall exhibited significantly elevated immune infiltration and PD-L1 protein expression. Immune profiling demonstrated that T-cell inflammation and adenosine signatures were significantly higher in CD73-expressing lung adenocarcinomas relative to those lacking CD73. Conclusion Our study suggests that higher CD73 expression is associated with an overall augmented host immune response, suggesting potential implications in the immune pathobiology of early stage lung adenocarcinoma. Our findings warrant further studies to explore the role of CD73 in immunotherapeutic response of LUAD.

Twenty-five cases of micronodular thymomas with prominent cystic changes are presented. The patients are 13 men and 12 women between the ages of 38 and 69 years. Clinically, the majority of patients presented with nonspecific symptoms of cough, chest pain, and dyspnea. Four patients were asymptomatic. Diagnostic imaging showed the presence of an anterior mediastinal mass and surgical resection of the tumor mass was performed in all the patients. Histologically, all the tumors were characterized by the presence of cystic structures of varying sizes lined by different types of epithelium. In addition, the tumors were characterized by nodules of epithelial cells embedded in a lymphocyte-rich stroma with germinal centers. Twenty-one tumors were encapsulated while 4 tumors were minimally invasive. Immunohistochemical stains were positive for keratin in the nodular epithelial component while CD45 and CD20 were positive in the lymphoid component. Clinical follow-up ranging from 12 to 24 months was obtained in 19 patients. All the patients were alive and well without disease. No clinical follow-up was available in 6 patients. The cases presented in this article highlight the existence of cystic micronodular thymomas, which can be easily misdiagnosed as a multilocular thymic cyst.

Background Small cell lung cancer (SCLC) has the strongest association with smoking among lung cancers. The characteristics of never smokers with SCLC is not known. Research Question Are the clinical characteristics, prognostic factors, survival, genomic alterations, and tumor mutational burdens of SCLC in patients who have never smoked different from those who have smoked? Study Design and Methods A retrospective multicenter cohort study of patients with clinician-confirmed SCLC was performed with the use of a longitudinal and nationally representative electronic medical records database. Smoking history was assessed through technology-enabled abstraction and confirmed for never smokers via chart review. Genomic characteristics of never smoker patients with SCLC were examined with the use of a next-generation sequencing-based gene panel and whole exome sequencing. Results One hundred of 5,632 patients (1.8%) with SCLC were never smokers. Relative to smokers, never smokers were more likely to be female (66.0% vs 52.4%; P = .009) and present with extensive stage (70.0% vs 62.2%; P = .028). Never smokers had a higher proportion of patients in age groups 35 to 49 years (7.0% vs 3.0%; P = .006) and ≥80 years (17.0% vs 8.2%; P = .006). Known risk factors for lung cancer were found in Interpretation The sex- and age-specific distribution of SCLC among never smokers, along with differences that were identified by genomic analyses, suggests a distinct biology of SCLC in never smokers compared with smokers.

BACKGROUND: Mutations in the serine-threonine kinase LKB1/STK11 have been implicated in mediating resistance to checkpoint blockade among patients with advanced lung adenocarcinoma. We sought to examine the associations between clinicopathologic characteristics, tumor LKB1 expression, features of the immune microenvironment, and postoperative prognosis among patients with early-stage lung adenocarcinoma undergoing surgical therapy. METHODS: Formalin-fixed, paraffin-embedded specimens of patients undergoing resection of stage I-III, chemotherapy-naïve adenocarcinomas (1997–2008) were analyzed using tissue microarray sectioning. Sublobar resections were excluded. Intratumoral LKB1/STK11 expression was quantified as H-score. In a subset, tumor associated immune cell populations were quantified using whole tumor sections in peritumoral and intratumoral compartments. RESULTS: 104 patients met inclusion criteria. LKB1/STK11 expression (median H-score 102.9) was higher in women (median 123.3) than men (100.0, p=0.004) and in never-smokers (median 145.0) than former/current smokers (100.0, p=0.002). LKB1/STK11 expression was positively correlated with intratumoral infiltration of CD3(+) (r=0.351, P=0.005), CD4(+) (r=0.436, P

Mucous gland adenomas represent a small percentage of primary lung neoplasms. The accurate diagnosis of these benign tumors can be challenging not only on resected specimens but also more challenging in small bronchoscopic biopsies. If to that problem we add the issue that these tumors may also exist in the periphery of the lung, then it is easy to conclude that there is much difficulty in properly diagnosing these tumors with a core needle biopsy. Furthermore, there is little knowledge on the immunohistochemical properties and radiologic features of these tumors. Therefore, pathologists need to be aware of the spectrum of histopathologic features in these tumors and place them in perspective regarding the proper radiologic and immunohistochemical correlations. Needless to say, mucous gland adenomas exhibit a gamut of histopathologic features that can be easily confused with other more common tumor of the lung. Therefore, awareness of such features become essential in a benign tumor that is essentially diagnosed on morphologic grounds.

Purpose: Nintedanib enhances the activity of chemotherapy in metastatic non–small cell lung cancer (NSCLC). In this phase I/II study, we assessed safety and efficacy of nintedanib plus neoadjuvant chemotherapy, using major pathologic response (MPR) as primary endpoint. Patients and Methods: Eligible patients had stage IB (≥4 cm)–IIIA resectable NSCLC. A safety run-in phase was followed by an expansion phase with nintedanib 200 mg orally twice a day (28 days), followed by three cycles of cisplatin (75 mg/m2), docetaxel (75 mg/m2) every 21 days plus nintedanib, followed by surgery. With 33 planned patients, the study had 90% power to detect an MPR increase from 15% to 35%. Results: Twenty-one patients (stages I/II/III, N = 1/8/12) were treated. One of 15 patients treated with nintedanib 200 mg achieved MPR [7%, 95% confidence interval (CI), 0.2%–32%]. Best ORR in 20 evaluable patients was 30% (6/20, 95% CI, 12%–54%). Twelve-month recurrence-free survival and overall survival were 66% (95% CI, 47%–93%) and 91% (95% CI, 79%–100%), respectively. Most frequent treatment-related grade 3–4 toxicities were transaminitis and electrolyte abnormalities. On the basis of an interim analysis the study was discontinued for futility. Higher levels of CD3+ and cytotoxic CD3+CD8+ T cells were found in treated tumors of patients who were alive than in those who died (652.8 vs. 213.4 cells/mm2, P = 0.048; 142.3 vs. 35.6 cells/mm2, P = 0.018). Conclusions: Although tolerated, neoadjuvant nintedanib plus chemotherapy did not increase MPR rate compared with chemotherapy historical controls. Additional studies of the combination in this setting are not recommended. Posttreatment levels of tumor-infiltrating T cells were associated with patient survival. Use of MPR facilitates the rapid evaluation of neoadjuvant therapies. See related commentary by Blakely and McCoach, p. 3499

Introduction We have suggested that major pathologic response (MPR) could serve as a surrogate endpoint for survival and provide rapid means of comparing different neoadjuvant treatment regimens. Here, we confirm that MPR is predictive of long-term overall survival (OS) in patients with non–small-cell lung cancer (NSCLC) who underwent neoadjuvant chemotherapy and surgical resection, to assess agreement on MPR between 2 observers, and to determine the minimum number of slides needed to obtain an accurate determination of MPR. Patients and Methods We identified 151 patients with NSCLC who had been treated with neoadjuvant chemotherapy followed by complete surgical resection from 2008 to 2012. Tissue specimens were retrospectively evaluated by 2 pathologists who had been blinded to patients’ treatment and outcome. We assessed the relationships between MPR and OS, the levels of agreement between the pathologists, and determined the number of slides needed to obtain an accurate determination of MPR. Results Our results reveal that MPR examined by either observer 1 (experienced) or by observer 2 (trained) was significantly predictive of long-term OS after neoadjuvant chemotherapy. MPR was associated with long-term OS in patients with NSCLC undergoing neoadjuvant chemotherapy on multivariable analysis (hazard ratio 2.68; P = .01). The levels of agreement between 2 pathologists were high after direct in-person training by one pathologist or the other (R2 = 0.994). Our data suggest that at least 3 slides should be read to accurately determine MPR. Conclusions MPR is significantly predictive of long-term OS in neoadjuvant chemotherapy–treated patients with NSCLC. MPR may serve as a surrogate endpoint for evaluating novel chemotherapies and immunotherapy response in biomarker-driven translational clinical trials.

Enhanced tumor glycolytic activity is a mechanism by which tumors induce an immunosuppressive environment to resist adoptive T cell therapy; therefore, methods of assessing intratumoral glycolytic activity are of considerable clinical interest. In this study, we characterized the relationships among tumor (18)F-fluorodeoxyglucose (FDG) retention, tumor metabolic and immune phenotypes, and survival in patients with resected non-small cell lung cancer (NSCLC). We retrospectively analyzed tumor preoperative positron emission tomography (PET) (18)F-FDG uptake in 59 resected NSCLCs and investigated correlations between PET parameters (SUV(Max), SUV(Total), SUV(Mean), TLG), tumor expression of glycolysis- and immune-related genes, and tumor-associated immune cell densities that were quantified by immunohistochemistry. Tumor glycolysis-associated immune gene signatures were analyzed for associations with survival outcomes. We found that each (18)F-FDG PET parameter was positively correlated with tumor expression of glycolysis-related genes. Elevated (18)F-FDG SUV(Max) was more discriminatory of glycolysis-associated changes in tumor immune phenotypes than other (18)F-FDG PET parameters. Increased SUV(Max) was associated with multiple immune factors characteristic of an immunosuppressive and poorly immune infiltrated tumor microenvironment, including elevated PD-L1 expression, reduced CD57(+) cell density, and increased T cell exhaustion gene signature. Elevated SUV(Max) identified immune-related transcriptomic signatures that were associated with enhanced tumor glycolytic gene expression and poor clinical outcomes. Our results suggest that (18)F-FDG SUV(Max) has potential value as a noninvasive, clinical indicator of tumor immunometabolic phenotypes in patients with resectable NSCLC and warrants investigation as a potential predictor of therapeutic response to immune-based treatment strategies.

Five cases of an unusual primary benign stromal tumor designated as hemangioblastoma-like clear cell stromal tumor of the lung are presented. The patients are 4 women and 1 man between the ages of 39 and 52 years of age (average: 45.5 y). The patients presented with nonspecific symptoms of cough, chest pain, or dyspnea. None of the patients had any prior history of malignancy or tumor elsewhere. Diagnostic imaging showed the presence of an intrapulmonary tumor. Lobectomy was performed in all 5 patients. Grossly, the tumors were well-demarcated but not encapsulated with focal areas of hemorrhage without necrosis. Histologically, low power examination showed a cellular proliferation alternating with discrete dilated vessels reminiscent of a vascular neoplasm. Higher magnification showed medium-sized cells with clear cytoplasm arranged in sheets and cords. Mitotic activity and marked cellular atypia were not present. A wide panel of immunohistochemical studies was performed including epithelial, neural, muscle, vascular, and neuroendocrine markers, all of which showed negative staining. Tumor cells showed positive staining for vimentin. In 2 cases, fluorescence in situ hybridization for the solitary fibrous tumor was performed and was negative. Clinical follow-up in 3 patients showed no evidence of recurrence. The cases herein presented highlight an unusual benign stromal tumor of the lung, which needs to be considered in the differential diagnosis of tumors with a clear cell and vascular appearance.

Non-small cell lung cancer remains a highly lethal malignancy. Using the tamoxifen inducible Hnf1b:CreERT2 (H) transgenic mouse crossed to the LsL-KrasG12D (K) transgenic mouse, we recently discovered that an Hnf1b positive cell type in the lung is sensitive to adenoma formation when expressing a mutant KrasG12D allele. In these mice, we observe adenoma formation over a time frame of three to six months. To study specificity of the inducible Hnf1b:CreERT2 in the lung, we employed lineage tracing using an mTmG (G) reporter allele. This technique revealed recombined, GFP+ cells were predominantly SPC+. We further employed this technique in HKG mice to determine Hnf1b+ cells give rise to adenomas that express SPC and TTF1. Review of murine lung tissue confirmed a diagnosis of adenoma and early adenocarcinoma, a pathologic subtype of non-small cell lung cancer. Our expanded mouse model revealed loss of Mst1/2 promotes aggressive lung adenocarcinoma and large-scale proteomic analysis revealed upregulation of PKM2 in the lungs of mice with genetic deletion of Mst1/2. PKM2 is a known metabolic regulator in proliferating cells and cancer. Using a human lung adenocarcinoma cell line, we show pharmacologic inhibition of Mst1/2 increases the abundance of PKM2, indicating genetic loss or pharmacologic inhibition of Mst1/2 directly modulates the abundance of PKM2. In conclusion, here we report a novel model of non-small cell lung cancer driven by a mutation in Kras and deletion of Mst1/2 kinases. Tumor development is restricted to a subset of alveolar type II cells expressing Hnf1b. Our data show loss of Mst1/2 regulates levels of a potent metabolic regulator, PKM2.

Rationale: Uninvolved normal-appearing airway epithelium has been shown to exhibit specific mutations characteristic of nearby non–small cell lung cancers (NSCLCs). Yet, its somatic mutational landscape in patients with early-stage NSCLC is unknown. Objectives: To comprehensively survey the somatic mutational architecture of the normal airway epithelium in patients with early-stage NSCLC. Methods: Multiregion normal airways, comprising tumor-adjacent small airways, tumor-distant large airways, nasal epithelium and uninvolved normal lung (collectively airway field), matched NSCLCs, and blood cells (n = 498) from 48 patients were interrogated for somatic single-nucleotide variants by deep-targeted DNA sequencing and for chromosomal allelic imbalance events by genome-wide genotype array profiling. Spatiotemporal relationships between the airway field and NSCLCs were assessed by phylogenetic analysis. Measurements and Main Results: Genomic airway field carcinogenesis was observed in 25 cases (52%). The airway field epithelium exhibited a total of 269 somatic mutations in most patients (n = 36) including key drivers that were shared with the NSCLCs. Allele frequencies of these acquired variants were overall higher in NSCLCs. Integrative analysis of single-nucleotide variants and allelic imbalance events revealed driver genes with shared “two-hit” alterations in the airway field (e.g., TP53, KRAS, KEAP1, STK11, and CDKN2A) and those with single hits progressing to two in the NSCLCs (e.g., PIK3CA and NOTCH1). Conclusions: Tumor-adjacent and tumor-distant normal-appearing airway epithelia exhibit somatic driver alterations that undergo selection-driven clonal expansion in NSCLC. These events offer spatiotemporal insights into the development of NSCLC and, thus, potential targets for early treatment.

Context Invasive micropapillary adenocarcinoma (MPC) is an aggressive variant of lung adenocarcinoma, frequently manifesting with advanced stage lymph node metastasis and decreased survival. Objective Identification of this morphology is important, as it is strongly correlated with poor prognosis regardless of the amount of MPC component. To date, no study has investigated the morphological criteria used to objectively diagnose it. Design Herein, we selected 30 cases of potential MPC of lung, and distributed 2 digital images per case among 15 pulmonary pathology experts. Reviewers were requested to diagnostically interpret, assign the percentage of MPC component, and record the morphological features they identified. The noted features included: columnar cells, elongated slender cell nests, extensive stromal retraction, lumen formation with internal epithelial tufting, epithelial signet ring-like forms, intracytoplasmic vacuolization, multiple nests in the same alveolar space, back-to-back lacunar spaces, epithelial nest anastomosis, marked pleomorphism, peripherally oriented nuclei, randomly distributed nuclei, small/medium/large tumor nest size, fibrovascular cores, and spread through air-spaces (STAS). Results Cluster analysis revealed three subgroups with the following diagnoses: “MPC”, “combined papillary and MPC”, and “others”. The subgroups correlated with the reported median percentage of MPC. Intracytoplasmic vacuolization, epithelial nest anastomosis/confluence, multiple nests in the same alveolar space, and small/medium tumor nest size were the most common criteria identified in the cases diagnosed as MPC. Peripherally oriented nuclei and epithelial signet ring-like forms were frequently identified in both the “MPC” and “combined papillary and MPC” groups. Conclusions Our study provides objective diagnostic criteria to diagnose MPC of lung.

Fibrosing lesions of the mediastinum represent a small but challenging group of lesions that range in etiology from infectious to idiopathic to neoplastic. The diagnosis of such lesions becomes more challenging in the setting of mediastinoscopic biopsies. In addition, over the years, there has been further accumulation of knowledge of the clinical aspects of these lesions that needs to be incorporated into their evaluation. Therefore, it is essential that in the general evaluation of these fibrosing processes, one not only carefully examines the histopathologic features of the lesion, that of a fibroinflammatory process with the appropriate histochemical and immunohistochemical studies, but also carefully evaluates the clinical presentation and imaging findings. Needless to say, as will be illustrated in this review, determining a definitive unequivocal diagnosis on a small mediastinoscopic biopsy may be difficult, and often one needs to provide guidance on the perspective of the histologic features present. In some cases, mainly tumoral conditions with extensive fibrosis, a conclusive diagnosis can be made; however, it is those cases in which the extensive fibrosis is the only histopathologic feature where more appropriate guidance is required. While this review will focus more on the non-neoplastic fibroinflammatory lesions of the mediastinum, within the discussion of differential diagnoses, we will discuss some neoplastic conditions that commonly show extensive fibrosing features.

ObjectivesEight cases of encapsulated and cystic atypical thymomas (World Health Organization type B3) are presented.MethodsCases were identified after review of more than 500 thymomas. Histologic material from surgical resections was evaluated.ResultsThe patients are seven men and one woman aged 43 to 71 years. Seven patients presented with nonspecific symptoms while one mass was found on autopsy. The tumors were 4 to 6 cm in greatest dimension and showed prominent cystic changes with an epithelial proliferation arranged in sheets and cords. Increased mitotic activity and nuclear pleomorphism were not identified. All tumors were encapsulated. Immunohistochemical studies showed the tumor cells positive for keratin cocktail, keratin 5/6, and p63. Clinical follow-up was available in five patients. All were alive without recurrence.ConclusionsThese cases represent an unusual variant of atypical thymoma that can be misdiagnosed as thymic carcinoma or multilocular thymic cyst. Awareness of this histologic growth pattern is important for accurate diagnosis.

Summary Three cases of primary carcinomas of the lung each with an extensive osteoclast-like giant cell component are presented. The patients are 3 men between the ages of 58 and 67 years (average, 62.5 years) who presented with nonspecific symptoms. A history of malignancy, infectious, or granulomatous disease was negative in all the patients. Diagnostic imaging disclosed the presence of a large intrapulmonary mass; in 1 case in the right upper lobe and in 2 cases in the right lower lobe. Surgical resection via lobectomy was performed in the 3 patients. Grossly, the tumors were described as soft, friable intrapulmonary masses, reddish in color, and measuring from 6 to 13 cm in largest diameter. Histologically, the tumors were each characterized by the extensive presence of a multinucleated osteoclast-like giant cell component, which represented approximately 80% of the tumor mass. The osteoclast-like giant cell component was admixed with a sarcomatoid carcinoma in 2 cases and an adenocarcinoma in 1 case. Immunohistochemistry showed that the osteoclast-like giant cells were positive for CD-68, cathepsin K, and histone H3, whereas the carcinoma component was positive for keratin, thyroid transcription factor-1, and histone H3 (patchy). Molecular studies were performed in 2 patients with negative results. Clinical follow-up was obtained in 2 patients; 1 died 14 months after initial diagnosis, whereas 1 remains alive 6 months after initial diagnosis. One patient was lost to follow-up. The current neoplasms represent an unusual type of lung carcinoma that needs highlighting as a separate type from conventional giant cell carcinoma.

OBJECTIVES Ten cases of thymomas with an extensive xanthomatous component are presented. METHODS Cases were identified during a review of more than 500 cases of thymomas. Histologic material from surgical resections was evaluated. RESULTS The patients included five men and five women aged 47 to 64 years who had nonspecific symptoms. Grossly, all tumors were solid, measuring 2.5 to 4.5 cm. Eight tumors were encapsulated; two were minimally invasive. Histologically, the tumors showed varying histologies, all with an extensive xanthomatous component comprising 50% to 80% of the tumor. Immunohistochemical stains showed tumor cells positive for keratin and keratin 5/6 while the xanthomatous component was positive for CD68. Follow-up information showed nine patients remain alive with no recurrence. No follow-up information was obtained in one patient. CONCLUSIONS The presence of an extensive xanthomatous component may pose difficulties in the interpretation of these tumors. This study highlights the importance of proper sampling and awareness of this unusual feature.

Cystic lesions of the anterior mediastinum represent a well-known group of benign lesions that are relatively common in the general practice, namely in the pediatric age group. In the adult population, multilocular thymic cyst (MTC) plays an important role in occurrence as it presents as a cystic anterior mediastinal mass that clinically may mimic another anterior mediastinal tumor. In general, MTC is of rather unusual occurrence and its histopathological features have been well described in the literature. However, similar histopathological features may also be associated with a gamut of other tumoral conditions that although unrelated may be encountered growing along the walls of these cystic structures. Herein a presentation of the classical MTC and the classical histopathological features of such entity in association with other tumoral conditions will be discussed. It is highly important to underscore that the final interpretation of some of these tumors is based on a thorough evaluation of the cystic lesion and a reasonable sampling for histological evaluation so that the proper interpretation can be reached. Needless to say, the radiological and clinical information of the patients with cystic anterior mediastinal lesions is very important in the final analysis of these cases.

Histology plays an essential role in therapeutic decision-making for lung cancer patients. However, the molecular determinants of lung cancer histology are largely unknown. We conducted whole-exome sequencing(WES) and microarray profiling on 19 micro-dissected tumor regions of different histologic subtypes from 9 patients with lung cancers of mixed histology. A median of 68.9% of point mutations and 83% of copy number aberrations were shared between different histologic components within the same tumors. Furthermore, different histologic components within the tumors demonstrated similar subclonal architecture. On the other hand, transcriptomic profiling revealed shared pathways between the same histologic subtypes from different patients, which was supported by the analyses of the transcriptomic data from 141 cell lines and 343 lung cancers of different histologic subtypes. These data suggest that histology of lung cancers may be determined at the transcriptomic level rather than the genomic level.

Fifty-three cases of sarcomatoid pleural mesothelioma were evaluated for CDKN2A (p16) homozygous deletion and correlated with BRCA-associated protein-1 (BAP1) expression by immunohistochemistry. The patients are 45 men and 8 women between the ages of 37 and 79 years (average age: 58 years), who presented with symptoms of chest pain, cough, and weight loss. Diagnostic imaging showed the presence of diffuse pleural thickening with encasement of the lung parenchyma in all the cases. All patients were surgically treated with extrapleural pneumonectomy. Loss of BAP1 reactivity was seen in 49 tumors and p16 homozygous deletion was seen in 41 tumors, while in 16 patients either BAP1 or p16 were noncontributory to the diagnosis of mesothelioma. However, we were able to detect a better survival rate in those patients in whom BAP1 was lost and p16 showed homozygous deletion. Our findings showed that even though the use of BAP1 and p16 are important tools in the diagnosis of mesothelioma, a proportion of cases still remains negative with approximately 30 % of the cases in which the concordance of BAP1 loss and p16 homozygous deletion will not be present. We consider that the final diagnosis of mesothelioma is best accomplished by a global interpretation of clinical, radiographic, and pathological features including immunohistochemistry and molecular studies.

Pulmonary sarcomatoid carcinoma (PSC) contains carcinomatous component (CaC) and sarcomatous component (SaC). Herein, we explored the genomic origin and intratumor heterogeneity (ITH) of PSC. We collected 31 resected PSC tumors and obtained CaC and SaC by laser capture microdissection for next-generation sequencing. The majority of PSCs (97%) had component-shared alterations. Driver mutations in EGFR, KRAS, MET, PIK3CA, and EML4-ALK fusion were mostly component-shared. Twenty-seven (87%) PSCs had component-private alterations. Compared with pure lung adenocarcinoma (LUAD), adenocarcinoma component of PSC showed lower EGFR incidence. Compared with other typical sarcomas, numerous genes of SaC exhibited significant differences. CaC and SaC had equivalent and proportional tumor mutation burden (TMB), as well as PD-L1 level. Compared with LUAD, SaC had significant higher TMB and more patients with high PD-L1 expression (tumor proportion score ≥50%). PSC with lower proportion of component-shared alterations (trunk-ratio) had a prolonged disease-free survival (DFS), regardless of the influence of clinical factors. We conclude that most PSCs originate from a monoclone accompanied by genomic ITH which is a potential independent prognostic factor, and more proportion of PSCs may be beneficial from immune checkpoint inhibitors.

Seven primary thymic epithelial neoplasms, 3 thymomas and 4 thymic carcinomas, with rhabdomyomatous component are herein described. The patients are 2 women and 5 men between the ages of 42 and 62 years (average, 52 years). Clinically, the patients presented with nonspecific symptoms of cough, chest pain, and dyspnea. None of the patients had history of myasthenia gravis or of previous malignancy. Diagnostic imaging revealed the presence of an anterior mediastinal mass in all the patients. Surgical resection was accomplished in all the cases. The 3 thymoma cases were encapsulated tumors: histologically, 2 were lymphocyte rich (World Health Organization type B1), and 1 was an atypical thymoma (World Health Organization type B3). All the thymic carcinomas were ill-defined tumor masses with infiltrative borders and histologically were high-grade carcinomas. In each tumor, in different proportion, there were easily identifiable areas with rhabdomyomatous component characterized by larger cells with eosinophilic cytoplasm and eccentrically placed nuclei. Immunohistochemical stains in all cases showed clearly demarcated presence of the epithelial component (keratin positive/desmin and myoglobin negative) and the rhabdomyomatous component (desmin and myoglobin positive/keratin negative). The 3 patients with thymoma are alive and without recurrence 3 and 5 years after surgical resection, whereas 3 patients with carcinoma died between 2 and 3 years after surgical resection. One patient with thymic carcinoma was lost to follow-up. The current cases highlight the ubiquitous distribution of myoid cells in different types of thymic epithelial neoplasms.

Background The tumor immune microenvironment of lepidic-pattern adenocarcinoma remains poorly understood. In this study, we characterized tumor infiltrating lymphocytes (TILs) and percent PD-L1 expression among adenocarcinoma presenting as either radiographic ground glass opacities (GGOs) or solid lesions. Methods Pathologic specimens of patients with clinical stage I lung adenocarcinoma were analyzed using tissue microarray sectioning. The invasive portion of the tumor was selected for the tissue core. Lepidic growth pattern was confirmed among the GGO lesions using whole section analysis. Progression was defined as pN+ or subsequent recurrence. Results A total of 181 patients were identified, among whom 13 (7%) represented GGOs without clinical progression, 113 (62%) represented radiographic solid lesions that never progressed, and 55 (30%) represented radiographic solid lesions that ultimately did progress. CD57+ cell density, a marker for antigen-specific, oligoclonal T cells and NK cells, differed among the three cohorts, with the highest cell density observed within radiographically solid lesions without progression, and lower cell density both in the radiographic solid lesions that progressed and GGOs. Other TIL phenotypes were not statistically different between cohorts. Of substantial clinical interest, median percent PD-L1 positive cells within GGOs was 14, whereas that of radiographic solid lesions without progression was 22, and radiographic solid lesions that subsequently progressed was 27 (P=0.07). Conclusions Lepidic pattern adenocarcinoma presenting as GGOs and radiographic solid lesions show differential immune regulation. Further studies to investigate whether GGOs representing adenocarcinoma have varying susceptibility to immune checkpoint inhibitor therapy are warranted.

We present 783 surgical resections of typical and atypical carcinoid tumors of the lung identified in the pathology files of 20 different pathology departments. All cases were critically reviewed for clinical and pathological features and further correlated with clinical outcome. Long-term follow-up was obtained in all the patients and statistically analyzed to determine significance of the different parameters evaluated. Of the histopathological features analyzed, the presence of mitotic activity of 4 mitoses or more per 2mm2, necrosis, lymphatic invasion and lymph node metastasis were identified as statistically significant. Tumors measuring 3 cm or more were also identified as statistically significant and correlate with clinical outcome. Based on our analysis, we consider that the separation of low and intermediate grade neuroendocrine neoplasms of the lung needs to be readjusted in terms of mitotic count as the risk of over grading these neoplasms exceeds 10% under the current criteria. We also consider that tumor size is an important feature to be considered in the assessment of these neoplasms and together with the histological grade of the tumor offers important features that can be correlated with clinical outcome.

Thirteen cases of primary pulmonary adenofibromas are presented. The patients are 8 women and 5 men between the ages of 41 and 73 years (average: 57 y). The patients presented with nonspecific symptomatology or their tumor was identified during routine chest films. A wedge resection was performed in all cases with lymph node sampling. Grossly, the tumors varied in size from 1 to 2.5 cm in greatest dimension. The entire tumor was histologically evaluated in all cases. All the tumors shared similar histologic features namely leaf-like/phyllodes-like growth patterns with varying areas of sclerosis, focal inflammation, and entrapped epithelium. A wide panel of immunohistochemical studies was performed including epithelial, neural, muscle, and vascular markers, all of which showed negative staining. The tumors were positive only for vimentin in the stroma and keratin in the entrapped epithelium. Further evaluation in 6 cases using in situ hybridization for the solitary fibrous tumor was performed and was negative. Clinical follow-up in all the patients showed no evidence of recurrence or metastatic disease, during a period of 12 to 36 months. The current cases highlight the unusual occurrence of pulmonary adenofibromas and the importance of separating these tumors from other tumors that may have the potential to recur or metastasize. The use of proper immunohistochemical stains/molecular analysis aids in the proper classification of these tumors.

A case of a primary lung carcinoma with histologic and immunohistochemical features of a mammary carcinoma is presented. The patient is a 72-year-old man who presented with symptoms of cough and dyspnea. Diagnostic imaging showed a bronchial tumor in the left lower lobe that was surgically resected by a left lower lobectomy. The tumor was characterized by a homogenous cellular proliferation composed of small to medium-sized cells with round nuclei and inconspicuous nucleoli. Multiple immunohistochemical stains were performed, and the tumor was notably positive for estrogen receptor, progesterone receptor, GATA3, and pan-keratin, while molecular analysis showed somatic mutation in ARID1A. Clinical follow-up showed that the patient is alive and well 18 months post-surgical resection without evidence of recurrence or metastatic disease. Based on the overall features of this neoplasm, we consider that the tumor herein presented represents an unusual type of lung carcinoma that we refer to as primary mammary-like carcinoma of the lung.

Objectives Twelve cases of thymomas with prominent alveolar-like growth pattern are presented. Methods The 12 cases were identified during a review of more than 350 cases of thymomas. Results The patients were five women and seven men between the ages of 48 and 69 years (mean, 58.5 years). Clinically, all patients presented with nonspecific symptoms. Grossly the tumors varied in size from 3.5 to 5 cm in greatest diameter. Histologically, all tumors showed a predominant alveolar-like growth pattern without a significant lymphocytic component. Immunohistochemistry showed positive staining for pan-keratin, keratin 5/6, and p63. Clinical follow-up showed that nine patients have remained alive and well with no recurrence, while no follow-up was obtained in three patients. Conclusions The cases herein described highlight the spectrum of growth patterns that thymomas may show and also highlight the importance to keep thymomas in the differential diagnosis of tumor with prominent alveolar-like growth pattern.

Introduction The understanding of immune checkpoint molecules' co-expression in non–small cell lung carcinoma (NCLC) is important to potentially design combinatorial immunotherapy approaches. Methods We studied 225 formalin-fixed, paraffin-embedded tumor tissues from stage I-III NCLCs — 142 adenocarcinomas (ADCs) and 83 squamous cell carcinomas (SCCs) — placed in tissue microarrays. Nine immune checkpoint markers were evaluated; four (programmed death ligand 1 [PD-L1], B7-H3, B7-H4, and indoleamine 2,3-dioxygenase 1 [IDO-1]) expressed predominantly in malignant cells (MCs) and five (inducible T cell costimulator, V-set immunoregulatory receptor, T-cell immunoglobulin mucin family member 3, lymphocyte activating 3, and OX40) expressed mostly in stromal tumor-associated inflammatory cells (TAICs). All markers were examined using a quantitative image analysis and correlated with clinicopathologic features, TAICs, and molecular characteristics. Results Using above the median value as positive expression in MCs and high density of TAICs expressing those markers, we identified higher expression of immune checkpoints in SCC than ADC. Common simultaneous expression by MCs was PD-L1 + B7-H3 + IDO-1 in ADC and PD-L1 + B7-H3, or B7-H3 + B7-H4, in SCC. TAICs expressing checkpoint were significantly higher in current smokers than in never smokers. Almost all the immune checkpoint markers showed positive correlation with TAICs expressing inflammatory cell markers. KRAS -mutant ADC specimens showed higher expression of PD-L1 in MCs and of B7-H3, T-cell immunoglobulin mucin family member 3, and IDO-1 in TAICs than wild type. Kaplan-Meier survival curves showed worse prognosis in ADC patients with higher B7-H4 expression by MCs. Conclusions We found frequent immunohistochemical co-expression of immune checkpoints in surgically resected NCLC tumors and correlated with tumor histology, smoking history, tumor size, and the density of inflammatory cells and tumor mutational status.

Purpose Precision radiation therapy such as stereotactic body radiation therapy and limited resection are being used more frequently to treat intrathoracic malignancies. Effective local control requires precise radiation target delineation or complete resection. Lung biopsy tracts (LBT) on computed tomography (CT) scans after the use of tract sealants can mimic malignant tract seeding (MTS) and it is unclear whether these LBTs should be included in the calculated tumor volume or resected. This study evaluates the incidence, appearance, evolution, and malignant seeding of LBTs. Methods and materials A total of 406 lung biopsies were performed in oncology patients using a tract sealant over 19 months. Of these patients, 326 had follow-up CT scans and were included in the study group. Four thoracic radiologists retrospectively analyzed the imaging, and a pathologist examined 10 resected LBTs. Results A total of 234 of 326 biopsies (72%, including primary lung cancer [n = 98]; metastases [n = 81]; benign [n = 50]; and nondiagnostic [n = 5]) showed an LBT on CT. LBTs were identified on imaging 0 to 3 months after biopsy. LBTs were typically straight or serpiginous with a thickness of 2 to 5 mm. Most LBTs were unchanged (92%) or decreased (6.3%) over time. An increase in LBT thickness/nodularity that was suspicious for MTS occurred in 4 of 234 biopsies (1.7%). MTS only occurred after biopsy of metastases from extrathoracic malignancies, and none occurred in patients with lung cancer. Conclusions LBTs are common on CT after lung biopsy using a tract sealant. MTS is uncommon and only occurred in patients with extrathoracic malignancies. No MTS was found in patients with primary lung cancer. Accordingly, potential alteration in planned therapy should be considered only in patients with LBTs and extrathoracic malignancies being considered for stereotactic body radiation therapy or wedge resection.

Three cases of primary pulmonary adenocarcinoma with prominent lymphoid stroma and papillary features mimicking Warthin's tumor are presented. The patients are two women and one man ages 52, 62, and 74 years respectively. Clinically, the patients presented with non-specific symptoms of cough, dyspnea, and chest pain. Imaging showed the presence of an intrapulmonary mass in the right lower, right upper and left lower lobe. All patients underwent lobectomy. Histologically, the tumors were characterized by the presence of and oncocytic papillary growth pattern embedded in a lymphoid rich background. Immunohistochemical stains for TTF-1, keratin 7, and beta-catenin were positive in the epithelial component, while CD20 showed strong positive staining in the lymphoid component. In addition, CD4 and CD8 also showed positive staining in a ratio of 3-4:1, EBER was negative. Kras mutations with wild type EGFR were identified in one case. Clinical follow-up ranging from 8 to 24 months was obtained showing that all patients are alive without recurrence. The cases herein presented represent an unusual histological variant of primary lung adenocarcinoma, which closely mimics Warthin's tumor.

The original version of this article unfortunately contained a mistake.

While several molecular targets have been identified for adenocarcinoma (ACA) of the lung, similar drivers with squamous cell carcinoma (SCC) are sparse. We compared signaling pathways and potential therapeutic targets in lung SCC and ACA tumors using reverse phase proteomic arrays (RPPA) from two independent cohorts of resected early stage NSCLC patients: a testing set using an MDACC cohort (N=140) and a validation set using the Cancer Genome Atlas (TCGA) cohorts. We identified multiple potentially targetable proteins upregulated in SCC, including NRF2, Keap1, PARP, TrkB, and Chk2. Of these potential targets, we found that TrkB also had significant increases in gene expression in SCC as compared to adenocarcinoma. Thus, we next validated the upregulation of TrkB both in vitro and in vivo and found that it was constitutively expressed at high levels in a subset of SCC cell lines. Furthermore, we found that TrkB inhibition suppressed tumor growth, invasiveness and sensitized SCC cells to tyrosine kinase EGFR inhibition in a cell-specific manner.

Thymic epithelial neoplasms are rare tumors that are difficult to diagnose and treat. Programmed death 1 (PD-1) receptor and its ligand (PD-L1) are expressed by various malignancies and are considered a prognostic factor and immunotherapeutic target. We examined the expression of both antibodies in 100 thymic epithelial neoplasms to assess their use as a biomarker and to correlate their expression with clinicopathological parameters. Whole-tissue sections of 74 thymomas and 26 thymic carcinomas were examined. Expression of PD-1 and PD-L1 was evaluated by immunohistochemistry and scored by the percentage of positive T-cells or tumor cells, respectively. Cases with strong membranous reactivity of the antibody in ≥5% of T-cells (PD-1) or tumor cells (PD-L1), respectively, were considered positive. Expression of PD-1 was detected in 52/100 cases (52%) including 6/26 thymic carcinomas (23%) and 46/74 thymomas (62%). PD-L1 was positive in 61/100 cases (61%) including 14/26 thymic carcinomas (54%) and 47/74 thymomas (64%). A total of 82 cases (82%) showed expression of PD-1 or PD-L1. PD-1+ cases were associated with higher stage in thymic carcinoma (P=0.01) and PD-1- cases with thymic carcinoma histology (P=0.0014), whereas PD-L1+ cases were associated with neoadjuvant therapy in thymoma (P=0.0065). There was no statistical difference between PD-1 or PD-L1 expression status and other clinicopathological parameters including overall survival. PD-1 and/or PD-L1 are expressed in up to 82% of thymic epithelial neoplasms. These results confirm that these tumors should be considered for PD-1/PD-L1-targeted therapy, however their predictive value in terms of prognosis remains uncertain.

Primary mediastinal non-Hodgkin lymphomas (PM-NHLs) represent ∼5% of all non-Hodgkin lymphomas (NHLs) and comprise lymphomas of B-cell and T-cell origin. PM-NHLs are defined as involvement of mediastinal lymph nodes, thymus, and/or mediastinal organs (heart, lung, pleura, pericardium) by NHL without evidence of systemic disease at presentation. The clinical scenario is variable and depends on the lymphoma subtype. The radiologic presentation is also variable ranging from a mediastinal mass with or without superior vena cava syndrome, a pleural or a cardiac mass associated with effusion, or as an effusion only. The diagnosis of PM-NHLs can only be established by microscopic evaluation, and therefore, general pathologists should be aware of these tumors and familiar with their diagnostic approach. The most common anterior mediastinal NHLs (90% to 95%) are primary mediastinal (PM) large B-cell lymphoma and T-lymphoblastic lymphoma. Thymic marginal zone lymphoma and mediastinal gray zone lymphoma are very rare. The remainder PM-NHLs involving middle or posterior mediastinum include diffuse large B-cell lymphoma (DLBCL) and rare cases of T-cell lymphoma, including anaplastic large cell lymphoma and breast implant-associated anaplastic large cell lymphoma extending to the anterior mediastinum. Primary pleural and cardiac NHLs are mostly DLBCLs. Other rare subtypes of PM-NHLs include DLBCL associated with chronic inflammation/pyothorax-associated lymphoma, fibrin-associated DLBCL (both Epstein-Barr virus positive), and pleural and/or pericardial primary effusion lymphoma (human herpesvirus-8 positive/Epstein-Barr virus positive). We review the historical aspects, epidemiology, clinicoradiologic features, histopathology, immunohistochemistry, differential diagnosis, and relevant cytogenetic and molecular features of the remaining mediastinal B-cell lymphomas, including primary thymic marginal zone lymphoma of the mucosa-associated lymphoid tissue type, other PM small B-cell lymphomas, PM plasmacytoma, and the most relevant PM T-cell lymphomas.

BACKGROUND: The tumor immune microenvironment (TIME) of lung cancer brain metastasis is largely unexplored. We carried out immune profiling and sequencing analysis of paired resected primary tumors and brain metastases of non-small-cell lung carcinoma (NSCLC). PATIENTS AND METHODS: TIME profiling of archival formalin-fixed and paraffin-embedded specimens of paired primary tumors and brain metastases from 39 patients with surgically resected NSCLCs was carried out using a 770 immune gene expression panel and by T-cell receptor beta repertoire (TCRβ) sequencing. Immunohistochemistry was carried out for validation. Targeted sequencing was carried out to catalog hot spot mutations in cancer genes. RESULTS: Somatic hot spot mutations were mostly shared between both tumor sites (28/39 patients; 71%). We identified 161 differentially expressed genes, indicating inhibition of dendritic cell maturation, Th1, and leukocyte extravasation signaling pathways, in brain metastases compared with primary tumors (P

Prediction of disease prognosis is essential for improving cancer patient care. Previously, we have demonstrated the feasibility of using quantitative morphological features of tumor pathology images to predict the prognosis of lung cancer patients in a single cohort. In this study, we developed and validated a pathology image-based predictive model for the prognosis of lung adenocarcinoma (ADC) patients across multiple independent cohorts. Using quantitative pathology image analysis, we extracted morphological features from H&E stained sections of formalin fixed paraffin embedded (FFPE) tumor tissues. A prediction model for patient prognosis was developed using tumor tissue pathology images from a cohort of 91 stage I lung ADC patients from the Chinese Academy of Medical Sciences (CAMS), and validated in ADC patients from the National Lung Screening Trial (NLST), and the UT Special Program of Research Excellence (SPORE) cohort. The morphological features that are associated with patient survival in the training dataset from the CAMS cohort were used to develop a prognostic model, which was independently validated in both the NLST (n = 185) and the SPORE (n = 111) cohorts. The association between predicted risk and overall survival was significant for both the NLST (Hazard Ratio (HR) = 2.20, pv = 0.01) and the SPORE cohorts (HR = 2.15 and pv = 0.044), respectively, after adjusting for key clinical variables. Furthermore, the model also predicted the prognosis of patients with stage I ADC in both the NLST (n = 123, pv = 0.0089) and SPORE (n = 68, pv = 0.032) cohorts. The results indicate that the pathology image-based model predicts the prognosis of ADC patients across independent cohorts.

Immunotherapy targeting T cells is increasingly utilized to treat solid tumors including non-small cell lung cancer (NSCLC). This requires a better understanding of the T cells in the lungs of patients with NSCLC. Here, we report T cell repertoire analysis in a cohort of 236 early-stage NSCLC patients. T cell repertoire attributes are associated with clinicopathologic features, mutational and immune landscape. A considerable proportion of the most prevalent T cells in tumors are also prevalent in the uninvolved tumor-adjacent lungs and appear specific to shared background mutations or viral infections. Patients with higher T cell repertoire homology between the tumor and uninvolved tumor-adjacent lung, suggesting a less tumor-focused T cell response, exhibit inferior survival. These findings indicate that a concise understanding of antigens and T cells in NSCLC is needed to improve therapeutic efficacy and reduce toxicity with immunotherapy, particularly adoptive T cell therapy., Relevant features of T cell repertoire in human cancer remain to be delineated. Here the authors show, by TCR sequencing in a large cohort of lung cancer patients, that while a majority of T cell clones are shared between tumor and adjacent lung tissue, less frequent tumor-unique T cell clones correlate with worse prognosis.

Two cases of primary intrapulmonary hyalinizing spindle cell tumor with giant rosettes are presented. The patients are one woman and one man ages 37 and 42 years respectively. Both patients presented with non-specific symptoms of cough, dyspnea, and chest pain. Imaging revealed the presence of an intrapulmonary mass. One tumor was located in the left lower lobe while the other tumor was in the right upper lobe. Both patients underwent lobectomy. The tumors ranged from 2.4 to 3.0 cm in greatest dimension and were characterized by the presence of a bland spindle cell proliferation with areas of hyalinization and the presence of the so-called giant rosettes. Immunohistochemical stains were performed and the spindle cell component show positive staining for vimentin and negative staining for Bcl-2, CD34, STAT6, p40. Keratin immunohistochemical stain highlighted the entrapped alveolar epithelium while S-100 protein showed weak focal staining in the spindle cells. Both patients have remained alive and well without evidence of recurrence or metastasis for a period of 6 to 14 months post-surgical resection. The cases herein presented highlight the ubiquitous distribution of this tumor and underscores the importance of keeping this particular tumor in the differential diagnosis of spindle cell tumors of the lung.

The existence of primary salivary gland type tumors (SGTs), similar to those occurring in the major salivary glands, is well known in the thoracic cavity. When they occur in this anatomic area, these tumors more commonly arise from the lung. However, the existence of these tumors primarily affecting the thymus, although recognized in the literature, is rather not well documented or known. In addition, contrary to the primary lung SGTs, which are predominantly of the malignant type, these tumors when occur in thymus encompass a wider spectrum of biology ranging from benign to low grade, and high grade malignancy. The recognition of SGTs in the thymus, even though rare, is important to properly address treatment and prognosis. Herein, we will discuss the numerous benign a malignant SGTs that have been described in the thymus and highlight the difficulty that these tumors may pose when occurring in the thymic area.

Programmed cell death ligand (PD-L1) has been studied as a predictive immunotherapy biomarker. We investigated PD-L1 expression in the whole tumor and in tumor-infiltrating macrophages (TIMs) as a prognostic biomarker in surgically resected pathologic stage I non-small cell lung cancer. Pathologic specimen from 113 patients with stage I lung cancer (pT1-2a, N0, M0, tumor size 1-5 cm, 79 adenocarcinoma, 34 squamous cell carcinoma) were analyzed for PD-L1 expression in the tumor and in the TIMs using immunohistochemistry and image analysis. Statistics included recursive partitioning, univariable, multivariable, and Kaplan-Meier analyses. Patients whose tumors expressed4.7% PD-L1 (N = 87) experienced significantly better overall survival (OS) (P = 0.001) than patients with PD-L14.7% (N = 26). Patients with PD-L1 expression in macrophages 6.3% (N = 24) also experienced significantly better (P = 0.005) OS than patients with6.3% (N = 89). The best outcomes were observed in patients with low PD-L1 expression in both tumor and macrophages with 5-year OS of 94% (N = 17). Contrarily, patients with high PD-L1 expression in both tumor and macrophages experienced 5-year OS of 20% (N = 19). Low PD-L1 expression in the tumor and in the TIMs was independently associated with survival in multivariable analysis (P = 0.000 and P = 0.030, respectively). Lower PD-L1 % expression in the tumor and in the TIMs seems to be associated with significantly better OS in surgically resected stage I lung cancer. Additional studies are needed to validate PD-L1 as a prognostic biomarker in lung cancer and to study the mechanisms of intratumoral immune response.

Nine cases of ectopic hamartomatous thymoma are described. The patients were 5 men and 4 women aged 34 to 52 years (mean, 43 y). All patients presented with solitary lower neck masses ranging in size from 3.5 to 8.0 cm (mean, 5.4 cm). Grossly, the lesions were circumscribed and lobulated masses with a fleshy white cut surface; cystic changes were identified in 3 cases. Histologically, the tumors were composed of varying proportions of spindle cells arranged in fascicles, mature adipose tissue, and an epithelial component composed of squamoid elements and glandular or ductal structures. In 1 case, duct-like structures dominated the histologic picture. Structures reminiscent of Hassall corpuscles were identified in 2 cases. No overt malignant changes were seen, and the mitotic activity ranged from 0 to 2 mitoses per 10 high-power fields. Immunohistochemically, the spindle cells coexpressed CK5/6, CD34, and smooth muscle actin, whereas the squamous component was positive for CK5/6 only. Bcl-2 was variably expressed in the spindle and epithelial elements, whereas Pax8 and STAT6 were uniformly negative. Clinical follow-up revealed that all patients were alive and well 2 to 5 years after diagnosis. Ectopic hamartomatous thymomas are benign neoplasms with a wide morphologic spectrum. The histologic and immunohistochemical features are reminiscent of thymic derivation and suggest possible origin from remnants of the thymic anlage. Changes in the nomenclature may be advised to more specifically designate tumor differentiation and to avoid confusion with true thymomas as these represent entirely separate clinicopathologic entities.

Fourteen cases of primary intrathoracic glomus tumor and glomangiosarcoma are presented. The patients were 9 men and 5 women aged 36 to 63 years (mean, 49.5 years). Clinically, 11 patients presented with nonspecific symptoms including cough, hemoptysis, chest pain, and back pain while 3 patients were asymptomatic. Anatomically, 9 tumors were in an intrapulmonary location, 3 in the mediastinum, and 2 in the trachea. Surgical resection was performed in all cases, and grossly the tumors varied in size from 1.5 to 4.5 cm in greatest diameter. Histologically, 12 cases corresponded to glomus tumor characterized by a homogenous proliferation of medium-sized cells with round nuclei and inconspicuous nucleoli and no evidence of mitotic activity or necrosis. In 2 cases, the presence of marked cellular pleomorphism, nuclear atypia, and mitotic activity was more in keeping with a diagnosis of glomangiosarcoma. The 2 glomangiosarcomas were located in the lung, one of which was associated with lymph node metastasis. Immunohistochemical stains for smooth muscle actin were positive in all cases while negative for epithelial, vascular, neuroendocrine, and neural markers. Clinical follow-up showed that all patients with a glomus tumor are alive and well after a period of 12 to 36 months after surgical resection. In contrast, the 2 patients with glomangiosarcoma died of tumor 24 and 36 months, respectively, after initial diagnosis. The current cases highlight the ubiquitous distribution of these tumors within the thoracic cavity and stress the importance of including these tumors in the differential diagnosis of thoracic neoplasms.

Objectives: Nine cases of thymomas with an extensive clear cell component are presented. Methods: The patients were six men and three women aged between 45 and 62 years (mean, 52 years). Presenting symptoms included shortness of breath, chest pain, and cough. Diagnostic imaging revealed anterior mediastinal masses in all patients, and all underwent thymectomy. Results: Grossly, the tumors varied from 3 to 9 cm in the greatest dimension. Four cases were invasive and five encapsulated. Histologically, the tumors were characterized by an epithelial cell component with extensive clear cell change, admixed with lymphocytes in varying proportions. Immunohistochemically, the tumors demonstrated the typical immunophenotype of thymomas characterized by positive staining of the epithelial cells for pancytokeratin and cytokeratin 5/6, absent expression of CD5 and c-kit, and reactivity of the lymphocytes for terminal deoxynucleotidyl transferase. Clinical follow-up available for six patients showed that all were alive and well 12 to 24 months after surgical resection. Conclusions: The cases herein presented highlight an unusual feature in thymoma that has more commonly been ascribed to thymic carcinoma. They also emphasize the importance of correct diagnosis to determine the appropriate treatment strategy and to accurately predict prognosis.

Visually normal cells adjacent to, and extending from, tumors of the lung may carry molecular alterations characteristics of the tumor itself, an effect referred to as airway field of cancerization. This airway field has been postulated as a model for early events in lung cancer pathogenesis. Yet the genomic landscape of somatically acquired molecular alterations in airway epithelia of lung cancer patients has remained unknown. To begin to fill this void, we sought to comprehensively characterize the genomic architecture of chromosomal alterations inducing allelic imbalance (AI) in the airway field of the most common type of lung tumors, non–small cell lung cancer (NSCLC). To do so, we conducted a genome-wide survey of multiple spatially distributed normal-appearing airways, multiregion tumor specimens, and uninvolved normal tissues or blood from 45 patients with early-stage NSCLC. We detected alterations in airway epithelia from 22 patients, with an increased frequency in NSCLCs of squamous histology. Our data also indicated a spatial gradient of AI in samples at closer proximity to the NSCLC. Chromosome 9 displayed the highest levels of AI and comprised recurrent independent events. Furthermore, the airway field AI included oncogenic gains and tumor suppressor losses in known NSCLC drivers. Our results demonstrate that genome-wide AI is common in the airway field of cancerization, providing insights into early events in the pathogenesis of NSCLC that may comprise targets for early treatment and chemoprevention. Cancer Res; 76(13); 3676–83. ©2016 AACR.